title: CYP3A5 genotype does not influence everolimus in vitro metabolism and clinical pharmacokinetics in renal transplant recipients.
abstract: BACKGROUND
  CYP3A5 genotyping might be useful to guide tacrolimus and sirolimus dosing. The aim of this study was to assess the influence of CYP3A5 polymorphism on everolimus metabolism and pharmacokinetics.
  
  
  METHODS
  We investigated the effect of CYP3A5 6986A>G polymorphism (CYP3A5*1/*3 alleles) on the pharmacokinetics of everolimus in 28 renal transplant patients and on its in vitro hepatic metabolism using a bank of genotyped human liver microsomes (n=49). We further evaluated in vitro the contribution of CYP3A4, CYP3A5, and CYP2C8 to everolimus hepatic metabolism using recombinant enzymes.
  
  
  RESULTS
  We found no association between CYP3A5 polymorphism and everolimus pharmacokinetics in renal transplant patients. On the other hand, no effect of CYP3A5 polymorphism was observed on the intrinsic clearance of everolimus by human liver microsomes, whereas that of tacrolimus (positive control) was 1.5-fold higher in microsomes carrying the CYP3A5*1 allele than in noncarriers. In vitro data showed that CYP3A4 is a better catalyst of everolimus metabolism than CYP3A5, whereas the opposite was observed for tacrolimus.
  
  
  CONCLUSIONS
  This study provides direct and indirect evidence that CYP3A5 genotyping cannot help improve everolimus therapy.
authors.affiliation: INSERM, UMR S-850, Limoges, France. nicolas.picard@unilim.fr
authors.forename: Nicolas
authors.initials: N
authors.lastname: Picard
authors.forename: Koukeb
authors.initials: K
authors.lastname: Rouguieg-Malki
authors.forename: Nassim
authors.initials: N
authors.lastname: Kamar
authors.forename: Lionel
authors.initials: L
authors.lastname: Rostaing
authors.forename: Pierre
authors.initials: P
authors.lastname: Marquet
mesh_terms: D000328:Adult; D000368:Aged; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D000068338:Everolimus; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D007166:Immunosuppressive Agents; D000068338:Everolimus; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D020123:Sirolimus